Repair of Acute Myocardial Infarction by Human Stemness Factors Induced Pluripotent Stem Cells

Abstract

Background-Nuclear reprogramming provides an emerging strategy to produce embryo-independent pluripotent stem cells from somatic tissue. Induced pluripotent stem cells (iPS) demonstrate aptitude for de novo cardiac differentiation, yet their potential for heart disease therapy has not been tested. Methods and Results-In this study, fibroblasts transduced with human stemness factors OCT3/4, SOX2, KLF4, and c-MYC converted into an embryonic stem cell-like phenotype and demonstrated the ability to spontaneously assimilate into preimplantation host morula via diploid aggregation, unique to bona fide pluripotent cells. In utero, iPS-derived chimera executed differentiation programs to construct normal heart parenchyma patterning. Within infarcted hearts in the adult, intramyocardial delivery of iPS yielded progeny that properly engrafted without disrupting cytoarchitecture in immunocompetent recipients. In contrast to parental nonreparative fibroblasts, iPS treatment restored postischemic contractile performance, ventricular wall thickness, and electric stability while achieving in situ regeneration of cardiac, smooth muscle, and endothelial tissue.

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

“…There are significant similarities between cancer cells and iPSCs, which include certain molecular properties, the ability to self-renew, rapid unlimited proliferation, high telomerase activity, expression profiles, and epigenetic signatures (78). As one of the criteria for pluripotency, iPSCs are known to form teratomas in immunocompromised recipients after subcutaneous, intratesticular, or intramuscular injection (79,80). The teratoma-forming capability of the differentiated iPSCs derived from different adult tissues varied substantially and correlated with the number of residual pluripotent cells (81).…”

General Overview of the Seventh International Symposium on Stem Cell Therapy and Cardiovascular Innovations

“…When injected into the infarcted murine myocardium, iPS cells caused an increase in ejection fraction and prevented post-infarction remodeling whereas adult fibroblasts did not [4].…”

De NovoMyocardial Regeneration: Advances and Pitfalls

“…integrate and electromechanically couple with cardiomyocytes (8,81). In vitro studies showed that iPS cells formed functional cardiomyocytes with established hormonal regulation pathways and functionally expressed cardiac ion channels besides adopting ventricular phenotype (56).…”

“…Nelson et al have recently shown that intramyocardially delivered iPS cells engrafted and survived in the immunocompetent host myocardium without disrupting the cyto-architecture (81). These iPS cells were developed from murine fibroblasts after viral induction with Yamanaka quartet of pluripotency genes and they also showed inherent cardiogenic potential.…”